Microwave-Assisted Solvent-Free Synthesis of Ipsapirone

Article abstract of DOI:10.1002/jhet.3520

The currently applied synthetic methods of serotonin receptor ligands belonging to the group of long-chain arylpiperazines, including ipsapirone, require the use of toxic solvents and comprise numerous synthetic steps. Moreover, the reaction yield does not exceed 60% in the majority of cases. These factors lead to an increased energy consumption and negatively impact the environment. This paper describes a more environmentally friendly method of ipsapirone synthesis that we decided to use. Ipsapirone was obtained in two different methods. The first method involved N-alkylation of bromobutyl saccharin with 1-(2-pyrimidyl)piperazine dihydrochloride, while the second was a one-pot method. Neither of these requires the use of toxic and expensive solvents. A shortened synthesis time, not exceeding 10?min due to the use of microwave radiation, is also another advantage of these methods. The yield of the final product, ipsapirone, was 85% and 67% in the first and the second method, respectively. We also attempted to obtain ipsapirone using saccharin and arylpiperazine salt (method III) as starting materials, but to no avail in the tested conditions. As described herein, the green chemistry method for ipsapirone synthesis is rapid, cost-effective, and environment friendly.

Full text of DOI:10.1002/jhet.3520

Month 2019
Microwave-Assisted Solvent-Free Synthesis of Ipsapirone
*
Damian Kułaga,
Jolanta Jaśkowska,
and Radomir Jasiński
Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of
Technology, ul. Warszawska 24, 31-155 Kraków, Poland
*E-mail: dkulaga@chemia.pk.edu.pl
Received October 4, 2018
DOI 10.1002/jhet.3520
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
The currently applied synthetic methods of serotonin receptor ligands belonging to the group of long-
chain arylpiperazines, including ipsapirone, require the use of toxic solvents and comprise numerous syn-
thetic steps. Moreover, the reaction yield does not exceed 60% in the majority of cases. These factors lead
to an increased energy consumption and negatively impact the environment. This paper describes a more en-
vironmentally friendly method of ipsapirone synthesis that we decided to use. Ipsapirone was obtained in
two different methods. The first method involved N-alkylation of bromobutyl saccharin with
1-(2-pyrimidyl)piperazine dihydrochloride, while the second was a one-pot method. Neither of these requires
the use of toxic and expensive solvents. A shortened synthesis time, not exceeding 10 min due to the use of
microwave radiation, is also another advantage of these methods. The yield of the final product, ipsapirone,
was 85% and 67% in the first and the second method, respectively. We also attempted to obtain ipsapirone
using saccharin and arylpiperazine salt (method III) as starting materials, but to no avail in the tested condi-
tions. As described herein, the green chemistry method for ipsapirone synthesis is rapid, cost-effective, and
environment friendly.
J. Heterocyclic Chem., 00, 00 (2019).
© 2019 Wiley Periodicals, Inc.

D. Kułaga, J. Jaśkowska, and R. Jasiński
Vol 000
INTRODUCTION
a suitable solvent, such as DMF [9] or ACN [11] to
obtain a product with a yield below 60%. However,
ipsapirone can be obtained in another reaction.
N-Alkylation of bromobutyl saccharin with 1-(2-
pyrimidyl)piperazine dihydrochloride (Scheme 1) appears
to be the most obvious route. Moreover, ipsapirone can
also be synthesized in a one-pot approach by reacting
saccharin, 1,4-dibromobutane, and 1-(2-pyrimidyl)
piperazine dihydrochloride (Scheme 2). This approach is
advantageous by lack of need for intermediate isolation,
and resulting improvement of economic aspects of the
entire process. Having considered the previously
described economic and ecological aspects, we decided to
employ a cost-effective, innovative, and environmentally
According to reports by the World Health Organization
[1], depression and diseases affecting the central nervous
system (CNS) will be one of the main burdens hindering
the functioning of the human population [2,3]. Modern
methods of treatment for these conditions include using a
wide range of medications acting on the CNS, but each of
them can cause side effects, and as much as 30% of patients
do not respond to treatment at all. One of the known
compounds that can be used in the treatment of CNS
diseases is ipsapirone, belonging to the class of azapirones
[4]. Ipsapirone, 2-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)
butyl)benzo[d]isothiazol-3(2H)-one1,1-dioxide,
is
a
known ligand with anxiolytic, anti-depressive [3], and
anti-aggressive effects, and a partial antagonist of the 5-
HT1A receptor [5]. It can also be used to treat alcohol
dependence [6]. From a chemical point of view, the
discussed compound is a long-chain arylpiperazine,
composed of a pyrimidylpiperazine linked via a butyl
moiety to saccharin. Ipsapirone synthesis has not been
widely described in the literature and patents. One of
several known methods of ipsapirone synthesis, claimed
in a patent, consists of a four-step reaction [7]. Such
synthesis, however, requires the use of toxic and
expensive solvents such as dimethylformamide (DMF) or
oxygenate-derived reagents, and the entire process is
long, taking about 24 h. The total yield of ipsapirone is
less than 40%. In turn, another patent reports that
ipsapirone can be synthesized by an alkylation reaction of
N-bromobutyl saccharin and 1-(2-pyrimidyl)piperazine
dihydrochloride [6]. Similarly to the previous patent, the
inventors use toxic DMF as a solvent, and the synthesis
time is 1 h, with yield amounting to 34%. The scientific
literature provides a general method for the synthesis of
ipsapirone analogues [8–10] (but not ipsapirone itself) by
alkylation of saccharin with a suitable alkylarylpiperazine
salt. As already described herein, the standard method
requires mixing substrates with potassium carbonate and
friendly method:
reaction, simultaneously being part of a green chemistry
trend.
a
solvent-free microwave-assisted
RESULTS AND DISCUSSION
Chemistry. N-alkylation of saccharine.
The initial
stage of our research involved the development of an
efficient method for the synthesis of N-bromobutyl
saccharin 3 in a solvent-free microwave-assisted reaction.
In our previous papers, we described N-alkylation of
imides under conventional methodology, in a solvent-free
conditions [12]. Fiorinoa et al. [13] describes
a
microwave-assisted N-alkylation of saccharin 1, however,
with the use of solvents. In this paper, we decided to
combine these two methods and obtain an alkylated
saccharin 3 in solvent-free, microwave-assisted conditions
(Scheme 3). We have started our research with
determining the appropriate molar amounts of reactants.
As a starting point, 1 eq of saccharin 1, 3 eq of K2CO3 as
a base, and 1.1 eq of alkylating agent 2 were used.
Because reagents do not mix with each other, a phase
transfer catalyst, that is, 0.1 eq tert-butylammonium
bromide (TBAB), was used to facilitate the reaction. The
Scheme 1. Synthesis of ipsapirone according to method 1.
Scheme 2. Synthesis of ipsapirone according to (one-pot) method 2.
Journal of Heterocyclic Chemistry
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Microwave-Assisted Solvent-Free Synthesis of Ipsapirone
Scheme 3. N-Alkylation of saccharine. [Color figure can be viewed at wileyonlinelibrary.com]
reaction was carried out in the presence of 1 wt% DMF
relative to saccharin 1, which was used as a medium to
transfer microwave energy [14]. The synthesis time was
50 s. The results are summarized in Table 1 (items 1–4).
The progress of the reaction was monitored by thin-layer
chromatography (TLC). Average yield of reaction
(item 1) is caused by formation of significant amounts of
the disubstituted product 9. Excess of 1,4-dibromobutane
(item 2) increases the selectivity of the reaction toward
the formation of N-bromobutyl saccharine 3. Impurities
observed in TLC were not isolated. It has been
determined that the optimal excess of alkylation agent is
2.5 eq. Larger excess does not have a major effect on the
reaction progress and may cause problem issues with the
crystallization of the product. Because Jaśkowska et al.
[12] report that the optimal amount of potassium
carbonate in the N-benzylation of phthalimide is 3 eq,
while Fiorinoa et al. [13] uses only 1.5 eq of K2CO3 in
the alkylation reaction of saccharin 1, we decided to
study and describe the effect of the amount of base on
the reaction yield. The results are shown in Table 1
(items 5–8). Based on the TLC analysis, an increased
amount of potassium carbonate promotes formation of
impurities. When 1.5 eq of K2CO3 was used, we
observed only spots attributable to N-bromobutyl
saccharin 3 and traces of disubstituted product 9. In
addition, we decided to evaluate the effect of DMF
addition; therefore, a complete synthesis of N-bromobutyl
saccharine 3 was run without DMF addition. Having
analyzed by TLC, the reaction mixture after 50 s of
reaction, partial formation of product 3, and significant
amount of unreacted saccharin 1 were noticed. The
reaction was then continued for 2 min. After this time,
TLC indicated the presence of the desired product 3 a by-
product and other impurities. In this case,
9
N-bromobutyl-saccharin 3 was not isolated. Our research
also compared the effects of addition of ACN instead of
DMF, and NaOH and Et3N instead of K2CO3 as a base,
as well as the catalytic amounts of KI instead of TBAB.
In all the reactions with ACN, formation of numerous by-
products was observed in TLC. The desired product was
not isolated. Using NaOH as a base, TLC analysis
indicated that during the first 10 s of heating, only
product 3 was formed and the presence of unreacted
substrate 1 was observed as before, while longer reaction
times caused degradation of product 3 and led to
formation of vast amounts of impurities; in this case, the
product has not been isolated as well. Satisfactory results
(85% yield) were observed only in the case of using
triethylamine instead of potassium carbonate.
Synthesis of ipsapirone: Method 1. Ipsapirone analogues
obtained by N-alkylation were presented as an examples of
the conventional method, and microwave-assisted method
between appropriate bromoalkylimide and 1-(2-
pyrimidyl)piperazine dihydrochloride 4 and are well
known in the literature [15,16]. However, both of these
synthetic approaches need toxic solvents to be used.
Reaction times are also relatively long and, in microwave
syntheses, often exceed 1 h. The initial step of ipsapirone
5 synthesis using a solvent-free method supported by
microwave radiation is similar to this of N-bromobutyl
saccharin 3 synthesis described previously. In this
experiment, we determined the effect of addition of
various bases on the reaction yield, and the results are
presented in Table 2 (items 9–18). Values listed in the
table show that the synthesis of ipsapirone 5 gives higher
yields (of about 80%) in the presence of weak inorganic
bases, such as potassium carbonate or calcium hydroxide.
Carrying out the reaction in these conditions is also
advantageous in the context of reaction time, as the use
of K2CO3 shortened the reaction time to 1 min, while
reaction in the presence of Ca(OH)2 took 2 min. TLC
analysis indicated the presence of the main product
ipsapirone 5 and traces of 1-(2-pyrimidyl)piperazine
dihydrochloride 4, which was used in 10% molar excess.
Using stronger inorganic bases, such as sodium
hydroxide or potassium hydroxide, decreased the reaction
yield to a point where no final product was isolated. TLC
analysis revealed the presence of ipsapirone 5 traces and
Table 1
Impact of 1,4-dibromobutane and base amounts on the yield in N-alkyl-
ation reaction of saccharine.
Item
1,4-Dibromobutane (eq)
K2CO3 (eq)
Yield (%)
1
2
3
4
5
6
7
8
1.1
2.0
2.5
3.0
2.5
2.5
2.5
2.5
3
3
3
3
1.0
1.5
2.0
2.5
45
67
79
80
70
94
85
80
Journal of Heterocyclic Chemistry
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D. Kułaga, J. Jaśkowska, and R. Jasiński
Vol 000
Table 2
after prolonged heating for up to 10 min, although over
Impact of various bases and solvents (DMF/ACN) on the yield in
Ipsapirone synthesis.
this period, some mixtures get burned.
Synthesis of ipsapirone: Method 2 (one pot). So-called
one-pot synthesis is one of the approaches in organic
synthesis, which follows the principles of green
chemistry, allowing one to obtain compounds in a clean,
effective, economical, and quick manner [17]. In the case
of ipsapirone 5, the isolation step of N-bromobutyl-
saccharine 3 can be omitted, thus shortening the synthesis
time. Cybulski et al. [18] described the method for
Base
(3 eq)
DMF
ACN
Yield
(%)a
Item
(wt%)b
(wt%)c
9
K2CO3
K2CO3
K2CO3
Et3N
Et3N
Et3N
NaOH
NaOH
Ca(OH)2
Ca(OH)2
0.1
—
—
0.1
—
—
0.1
—
0.1
—
—
0.1
—
—
0.1
—
—
0.1
—
0.1
85
0
43
83
0
35
0
0
10
11
12
13
14
15
16
17
18
synthesis buspirone derivatives by
a simultaneous
reaction of 1-(2-pyrimidyl)piperazine dihydrochloride,
1,4-dibromobutane, and the corresponding imide. They
reported high reaction yields for the final product with
using xylene as a solvent and heating the mixture in a
flask. Encouraged by this report, we decided to obtain
ipsapirone 5 in a one-step reaction, without any solvents
used for enhancing the microwave-assisted reaction; 1 eq
of saccharin 1, 2.5 eq of 1,4-dibromobutane 2, and 1.1 eq
of 1-(2-pyrimidyl)piperazine dihydrochloride 4 were used
for the synthesis. The results are shown in Table 3.
Ipsapirone 5 yield (52%) was slightly lower compared
with the two-step synthesis, yet still acceptable. Lower
yield is mainly attributable to a troublesome removal of
1,4-dibromobutane 2 excess upon the purification stage.
TLC analysis of the reaction mixture revealed that
addition of potassium carbonate as a base leads to
75
0
aHydrochloride salt crystallized from acetone.
bReaction time of up to 2 min.
cReaction time of up to 10 min.
vast amounts of polar impurities. The mentioned weak
inorganic bases can be considered as environmentally
friendly, cost-effective, and easily available. Using
triethylamine as a base for ipsapirone 5 synthesis allowed
to obtain good yields over the reaction time of 2 min.
However, due to the toxicity of this compound, this
synthetic approach is not recommended. Investigating the
effects of using DMF as a medium facilitating the
reaction yielded interesting results. Reacting compounds
in the presence of DMF accelerated the process very
efficiently. In the case of K2CO3, the content of 1 wt% of
DMF allowed to obtain the final product 5 with an 85%
yield, while its absence reduced the yield of the reaction
by 43%. When DMF was changed to ACN, no reaction
progress was seen. Attempts to obtain ipsapirone 5 in the
presence of ACN were repeated with addition of K2CO3,
Ca(OH)2, NaOH, and Et3N gave no measurable effects.
The final product was absent in the TLC analysis, even
formation of a greater number of impurities when
compared with using triethylamine.
Synthesis of ipsapirone: Method 3. An alternative version
of the N-alkylation reaction allowing to obtain ipsapirone 5
is
a
reaction between of 8-(pyrimidin-2-yl)-5,8-
diazaspiro[4.5]decan-5-ium bromide 6 and saccharin 1.
Using a similar approach, Malinka et al. [19] obtained a
series of imide derivatives (Scheme 4) with a high yield
(60–80%), using potassium carbonate as a base and
xylene as a solvent. Based on this report, we decided to
check the yield of ipsapirone 5. First, we obtained
8-(pyrimidin-2-yl)-5,8-diazaspiro[4.5]decan-5-ium
bromide 6 by a conventional method described in the
literature [19,20]. For this part of the research, we applied
the same method as the one used for synthesis of
N-bromobutyl saccharin 3. The use of K2CO3 in line with
the literature reports failed to give the product of interest.
However, having exchanged K2CO3 to NaOH, we
obtained the desired product with an 83% yield. In this
case, 1 wt% addition of DMF was essential. Upon the
Table 3
Impact of various bases on the reaction yield.
Item
Base (3 eq)
Yield (%)a
b
19
20
21
K2CO3
52
67
60
Et3Nc
b
Ca(OH)2
aHydrochloride salt crystallized from acetone.
bReaction time of up to 2 min.
cReaction time of up to 10 min.
Scheme 4. Imide derivatives obtained by Cybulski et al. [18].
Journal of Heterocyclic Chemistry
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Microwave-Assisted Solvent-Free Synthesis of Ipsapirone
Scheme 5. Synthesis of ipsapirone and analogue according to method 3.
next stage, a possibility to obtain ipsapirone 5 was tested in
accordance with Scheme 5, with determination of the effect
of used bases (K2CO3, Et3N, and Ca(OH)2) and the reaction
time (1, 2, 5, and 10 min.) on the reaction yield. Ipsapirone
5 was not formed in any of the tested conditions, as shown
by TLC and HPLC. Saccharin 1, classified as moderately
nucleophilic, is not as easily alkylated as its analogue,
phthalimide 7, which is the probable reason for the
observed outcome. To check this further, we decided to
perform a similar synthesis with phthalimide 7 instead of
saccharin 1 (Scheme 5). In this reaction, 50% of the
substrate was converted to the desired product after just a
1 min. Conversion was confirmed by TLC and UPLC-MS
analyses. It was determined that the potentially attractive
way for ipsapirone 5 synthesis using 8-(pyrimidin-2-yl)-
efficient method for synthesis of ipsapirone 5 is a two-
step N-alkylation of saccharin 1 in the first step and then
N-bromobutyl saccharin 3 in the next. The one-pot
method also seems to be fast and somehow efficient;
however, difficulties with product separation may occur,
as 1,4-dibromobutane 2 is hard to eliminate. Conversely,
we failed to obtain ipsapirone 5 using method 3 due to
the moderate nucleophilic index for saccharin 1,
preventing it from reacting. This conclusion was
confirmed by quantum chemical calculations and the
successful reaction in which saccharin 1 was replaced by
phthalimide 7 (Scheme 5).
EXPERIMENTAL
5,8-diazaspiro[4.5]decan-5-ium bromide
6
is not
achievable in the tested conditions. This phenomenon can
be explained by the molecular electron density theory
[21], which in recent years has been successfully used to
explain the reactivity of components in numerous
different types of bimolecular reactions [22–24]. The
global nucleophilicity descriptors needed for this purpose
(N) were obtained by calculating B3LYP/6-31G (d), using
the equation proposed by Domingo [25]:
All the reactants were purchased from commercial
available suppliers. H NMR spectra were recorded using
1
Bruker 300 and 400 MHz apparatuses with TMS as an
internal standard. Melting points were determined with
Böetius apparatus. Waters UPLC with a PDA detector
and 1.7 μm Aquity HPLC BEH C18 column was used
for UPLC-MS analyses. Knauer HPLC with DAD
detector and C18 1.4 μm column was used in HPLC
analysis, with MeOH : H2O + formic acid (4:6 + 0.1%)
as a mobile phase. Analytical TLC was performed using
0.2 mm silica gel precoated aluminum sheets (60 F254,
Merck), and UV light at 254 nm was used for
visualization. SAMSUNG ME73M at 300–450 W of
power was used for all the microwave-assisted reactions.
N ¼ EHOMO ꢀ EHOMOðtetracyanoetheneÞ
The calculated value of N index for saccharine 1 was
1.31 eV, which classifies this compound as a marginal
nucleophile. On the other hand, phthalimide 7 belongs to
the group of moderate nucleophiles (N = 1.82 eV) on the
Domingo reactivity scale [26]. This differentiation clearly
explains why phthalimide 7 reacts in mild conditions,
while the desired product cannot be obtained from
saccharin 1.
2-(4-Bromobutyl)benzo[d]isothiazol-3(2H)-one1,1-dioxide
(3). Saccharine 1 (1 g, 5.46 mmol), potassium carbonate
(1.13 g, 8.18 mmol), and TBAB (0.17 g, 0.53 mmol) were
ground in the mortar. Next, 1,4-dibromobutane 2 (1.6 mL,
13.62 mmol) was added, followed by 53 μL of DMF.
Mixture was reacted in a microwave reactor at 300 W for
50 s. After this time, TLC indicated that the reaction
was completed. Mixture was purified via flash
chromatography using 100% hexane to 100% methanol
as eluents. Methanol phase was evaporated to dryness,
and crude product was crystallized from MeOH to give
1.65 g of pure product. Melting point 71–72°C (ref. 71–
CONCLUSION
Ipsapirone 5, a ligand acting on the CNS, was obtained
in line with the green chemistry principles, with reduction
or complete elimination of toxic and expensive solvents.
Implementing a microwave-assisted approach shortened
the synthesis time from a few hours to minutes. The most
1
72°C [27]); yield 95%; white solid; H NMR (300 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Kułaga, J. Jaśkowska, and R. Jasiński
Vol 000
CDCl3) δ 8.09–8.04 (m, 1H), 7.95–7.81 (m, 3H), 3.83 (t,
J = 6.7 Hz, 2H), 3.46 (t, J = 6.2 Hz, 2H), 2.05–1.97 (m,
4H). UPLC-MS: 98.9%, m/z = 318.
minutes. Insoluble inorganics were filtered off, and the
filtrate was evaporated to dryness. The resulting semi-
solid material was crystallized from i-PrOH. Melting
point 245–247°C (ref. 241.5–242.5°C [29]); yield 83%;
white solid; 1H NMR (400 MHz, CDCl3) δ 8.40 (d,
J = 4.8 Hz, 2H), 6.70 (t, J = 4.8 Hz, 1H), 4.22 (t,
J = 7.2 Hz, 4H), 4.13 (t, J = 7.2 Hz, 4H), 3.82 (t,
J = 3.9 Hz, 4H), 2.44–2.39 (m, 4H). UPLC-MS = 100%,
m/z = 219 [M-Brꢀ].
Synthesis of ipsapirone (5) (method 3). 8-(Pyrimidin-2-
yl)-5,8-diazaspiro[4.5]decan-5-ium bromide 6 (0.3 g,
1 mmol), potassium carbonate (0.41 g, 2.97 mmol),
TBAB (0.032 g, 0.1 mmol), and saccharine 1 (0.36 g,
2 mmol) were ground in the mortar; 23 μL of DMF was
added to the mixture, and the mixture was placed in the
microwave reactor and reacted at 300 W for 120 s. After
this time, TLC and UPLC-MS indicated the presence of
starting materials only.
Ipsapirone (5) (method 1). 2-(4-Bromobutyl)benzo[d]
isothiazol-3(2H)-one1,1-dioxide 3 (0.2 g, 0.63 mmol),
potassium carbonate (0.26 g, 1.89 mmol), TBAB
(0.029 g, 0.063 mmol), and 1-(2-pyrimidyl)piperazine
dihydrochloride 4 (0.15 g, 0.63 mmol) were ground in
the mortar; 6.45 μL of DMF was added, and the mixture
was reacted in the microwave reactor at on 300 W for
60 s. After this time, TLC indicated that the reaction was
completed. Mixture was diluted with water, extracted
with ethyl acetate (3 × 10 mL), and organic phases were
combined and evaporated. Crude product was dissolved
in acetone, acidified with 4 M HCl in dioxane and cooled
down in a freezer to obtain white crystals. The desired
product was obtained as a hydrochloride salt. Melting
point: 217–220°C (ref. 221–222°C [28]); yield 85%;
1
white solid; H NMR (300 MHz, DMSO-d6) δ 10.50 (s,
2-(4-(4-(Pyrimidin-2-yl)piperazin-1-yl)butyl)isoindoline-
1,3-dione (8).
8-(Pyrimidin-2-yl)-5,8-diazaspiro[4.5]
1H), 8.45 (d, J = 4.8 Hz, 2H), 8.16–7.97 (m, 4H), 6.77
(t, J = 4.8 Hz, 1H), 4.69 (d, J = 14.1 Hz, 2H), 3.79 (t,
J = 6.6 Hz, 3H), 3.58–3.51 (d, J = 12 Hz, 2H), 3.43–3.36
(d, J = 20 Hz, 2H), 3.18 (m, 2H), 3.02 (dd, J = 20.6 Hz,
8.9 Hz, 2H), 1.82 (m, 4H). UPLC-MS: 93%, m/z = 401.14.
decan-5-ium bromide 6 (0.3 g, 1 mmol), potassium
carbonate (0.41 g, 2.97 mmol), TBAB (0.032 g,
0.1 mmol), and phthalimide 7 (0.29 g, 2 mmol) were
ground in the mortar; 22 μL of DMF was added to the
mixture, and the mixture was placed in the microwave
reactor and reacted at 300 W for 60 s. After this time,
TLC indicated the presence of the desired product,
unreacted substrates, and impurities. Mixture was diluted
with water and extracted with ethyl acetate (3 × 10 mL),
and organic phases were combined and evaporated.
Crude product was crystallized from MeOH to give pure
product. Melting point 137–139°C (ref. 138–139°C [30]);
Ipsapirone (5) (“one-pot” method 2).
Saccharine 1
(0.5 g, 2.73 mmol), potassium carbonate (1.13 g,
8.18 mmol), and TBAB (0.087 g, 0.27 mmol) were
ground in the mortar. Next, 1,4-dibromobutane
2
(0.8 mL, 6.9 mmol) was added, followed by 33 μL of
DMF. Mixture was reacted in the microwave reactor at
300
W
for 50 s, then 1-(2-pyrimidyl)piperazine
dihydrochloride 4 (0.15 g, 0.63 mmol) was added and
mixed in with a spatula. Mixture was placed again in the
microwave reactor and reacted at 300 W for 120 s. After
this time, TLC indicated that the reaction was completed.
Mixture was diluted with water and extracted with ethyl
acetate (3 × 10 mL), and organic phases were combined
and evaporated. Crude product was dissolved in acetone,
acidified with 4 M HCl in dioxane and cooled down in a
1
55% yield; white solid; H NMR (300 MHz, CDCl3) δ
8.30 (s, 2H), 7.78 (d, J = 36.8 Hz, 4H), 6.47 (s, 1H),
3.77 (d, J = 25.4 Hz, 6H), 2.45 (d, J = 22.6 Hz, 6H),
1.66 (d, J = 47.0 Hz, 2H). UPLC-MS = 92%, m/z = 366
[m + H].
Acknowledgments. The authors would like to thank The
National Centre for Research and Development (Grant No.
LIDER/015/L-6/14/NCBR/2015) for providing financial support
for this project.
freezer. The desired product was obtained as
a
hydrochloride salt. Melting point: 216–219°C (ref. 221–
222°C [28]); yield 50%; white solid; UPLC-MS: 90%, m/
z = 401.52.
8-(Pyrimidin-2-yl)-5,8-diazaspiro[4.5]decan-5-ium bromide
(6). 2-(Piperazin-1-yl)pyrimidine dihydrochloride 4 (1 g,
REFERENCES AND NOTES
4.24 mmol), sodium hydroxide (0.5 g, 12.5 mmol), and
TBAB (0.13 g, 0.40 mmol) were ground in the mortar.
Next, 1,4-dibromobutane 2 (1.22 mL, 10.54 mmol) was
added, followed by 38 μL of DMF. Mixture was reacted
in the microwave reactor at 450 W for 2 × 60 s. After
this time, TLC indicated that the reaction was completed.
The reaction mixture was cooled down to room
temperature, diluted with i-PrOH, and boiled for a few
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